(PQ10) Do microbiota alter the epigenetic landscape in human genome

(PQ10) 微生物群会改变人类基因组的表观遗传景观吗

• 批准号: 9171885
• 负责人: Alex Y Strongin
• 金额: $ 25.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-13 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171885
• 关键词: Aberrant DNA Methylation; Address; Affect; Antibiotic Therapy; Bacteria; Benign; Biology; Cancer Biology; Cell Nucleus; Cell Wall; Cells; Chromosome Mapping; Chronic; Clinical; Colon; Colorectal Cancer; CpG Islands; CpG dinucleotide; Cytolysis; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; DNA Sequence Alteration; Data; Development; Disease; Enzymes; Epigenetic Process; Epithelial Cells; Evolution; Exploratory/Developmental Grant; Funding; Genes; Genetic; Genome; Genomic DNA; Genomics; Germ-Line Mutation; Goals; Habitats; Health; Human; Human Biology; Human Genome; Human body; Immune; Incidence; Individual; Infection; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; Methodology; Methylation; Methyltransferase; Modification; Mycoplasma; Mycoplasma Infections; Mycoplasma hyorhinis; Nature; Neoplastic Cell Transformation; Oncogenic; Organism; Osmotic Shocks; Patients; Penicillin Resistance; Phenotype; Positioning Attribute; Probability; Promoter Regions; Property; Proteins; Research; Role; Site; Somatic Mutation; Staging; Stem cells; System; Therapeutic; Tissue Sample; Tissues; Tumor Biology; Work; base; cancer cell; cancer risk; cancer stem cell; cancer therapy; cancer type; data mining; epigenome; genome-wide; human tissue; in vivo; innovation; microbial; microbiome; microbiota; novel; novel diagnostics; pathogen; pathogenic bacteria; precursor cell; prognostic; programs; response; trafficking; tumor; tumorigenesis; tumorigenic

PROJECT SUMMARY This application is in response to RFA-CA-15-009 to propose pioneering approaches to addressing PQ–10 “How do microbiota affect the response to cancer therapies?” Human biology is no longer focused only on human cells. Microbiomes at different body habitats are now considered an essential component of human biology, development, evolution, health and disease. Bacteria of the endogenous flora in the human body outnumber human cells by at least one order of magnitude. A plethora of symbiotic and pathogenic bacteria in different body habitats form the microbiome. Bacteria, including mycoplasmas, internalize and colonize human cells, thereby subverting the immune defense system and antibiotic treatment. Mycoplasmas are the smallest and simplest self-replicating organisms. Over 200 species of mycoplasma are distinguished from ordinary bacteria by their minute size, limited genome, and lack of a cell wall. The absence of a cell wall conveys some unique properties to mycoplasma including their resistance to penicillin and sensitivity to lysis and osmotic shock. The data by us and others imply that mycoplasma infections are associated with some cancer types, including colorectal cancer. This suggests the possible co-existence of mycoplasmas and tumors in vivo that affects the response to cancer therapies, or, alternatively, indicates that mycoplasma infections create a possible roadmap to multi-step malignant transformation via epigenetic reprogramming of the affected normal/stem cells. Our working hypothesis is that chronic mycoplasma infection in the gut eventually leads to epigenetic alterations in epithelial cells that may enhance the likelihood for neoplastic transformation. An alternative, but not an exclusive hypothesis, is that the mycoplasma infection accelerates an already on-going tumorigenesis through the induction of additional epigenetic abnormalities. Our goals are to pursue this innovative hypothesis. Our R21 program is based on volumes of our innovative experimental data characterizing epigenetic abnormalities, which are aberrantly introduced in the human genome by mycoplasmal 5-methylcytosine-DNA methyltransferases. Our Specific Aims are: (1) Demonstrate the presence of the aberrant, de novo genomic DNA methylation in host cells infected by M. hyorhinis, and (2) Determine the incidence of the genomic material of Mycoplasma hyorhinis and other mycoplasma species in tumor and normal human tissue samples. We are confident that our proposed studies will lead to paradigm- shifting results in host-pathogen interactions, human epigenetics and cancer onset, and that our project will have wide-ranging ramifications. Additionally, this knowledge will lead to novel diagnostic and prognostic approaches and therapeutic regiments in patients at risk of cancer development.

项目总结